This is an R21 proposal focusing on genetic variation and neuroimaging measures related to brain glutamate metabolism. Glutamate is a crucial neurotransmitter and abnormalities in the glutamate system have been reported in major psychiatric conditions including schizophrenia and bipolar disorder. Indeed, several candidate drugs modifying glutamatergic neurotransmission are under development as treatments for these conditions. This approach holds great promise, but we do not have a good understanding of the molecular determinants of glutamate metabolism or in vivo brain glutamate probes which can support drug development efforts. The PI is an R01 holder from NIMH whose research has focused on optimizing proton magnetic resonance spectroscopy (MRS) sequences for brain glutamate and glutamine quantification and on using MRS to probe regional glutamate dynamics in patient populations. He has recently begun collaborating with Dr. Jordan Smoller, a recognized expert on psychiatric genetics. This collaboration has resulted in recently published data indicating a relationship between variation in the glutaminase (the enzyme which converts glutamine to glutamate) gene GLS1 and the brain glutamine/glutamate ratio measured using MRS. Thus, genetic variation in GLS1 is associated with in vivo variation in the metabolite levels which GLS1 controls. Armed with a validated neuroimaging approach which allows us to quantify in vivo brain glutamate dynamics, we can now experimentally test this hypothesis in an adequately-powered healthy control sample. In Specific Aim 1 of this proposal, we propose to examine the relationship between variation in the GLS1 gene and regional brain glutamine/glutamate ratio in a sample of healthy control subjects. In Specific Aim 2, we will examine downstream consequences of glutamatergic abnormalities by testing whether GLS1 genetic variation is associated with levels of N-acetylaspartate, a marker of neuronal integrity and function. In future studies, we plan to determine whether GLS1 genetic variation interact differentially with psychiatric illness to generate abnormal glutamine/glutamate ratios in cohorts of patients with schizophrenia or bipolar disorder. Thus, we hope to explore the mechanisms of glutamatergic dysregulation in schizophrenia and bipolar disorder through molecular and neuroimaging analyses. These studies are designed to ultimately provide information about genetic and chemical abnormalities related to glutamatergic neurotransmission in two common, chronic, and severe psychiatric disorders and to aid drug development efforts by providing specific molecular targets and in vivo biomarkers of these abnormalities.